Method for rapidly preparing dapagliflozin crude product based on microchannel continuous flow technology

Abstract

The invention discloses a method for rapidly preparing a dapagliflozin crude product based on a microchannel continuous flow technology, which comprises the following steps: by taking 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4 '-ethyoxyl diphenylmethane and a reducing agent as raw materials, carrying out liquid-liquid two-phase reduction reaction in a microreactor to generate the dapagliflozin crude product, according to the present invention, the traditional kettle type reaction is changed into the continuous process, the reaction selectivity is substantially improved, the generation of the isomer is reduced, the amplification effect is inhibited to the maximum extent, the yield of the obtained product is more than 90%, the purity is more than 90%, and the safe, green and efficient method is provided for the synthesis of the dapagliflozin crude product.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and in particular relates to a method for rapidly preparing a crude dapagliflozin product based on microchannel continuous flow technology. Background Art

[0002] Dapagliflozin, namely (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, is a white to light yellow powder or granules with a molecular formula of C 21 H 25 ClO6, CAS No. 461432-26-8, molecular weight 408.88, its structural formula is as follows: Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to treat type 2 diabetes.

[0003] Dapagliflozin crude product is prepared via a reduction reaction using 2-chloro-5-(1-methoxy-D-glucopyranos-1-yl)-4′-ethoxydiphenylmethane as the raw material. Boron trifluoride etherate acts as a Lewis acid to catalyze the reduction of the terminal carbonyl methoxy group with triethylsilane. The β-isomer is the primary product, along with the α-isomer. A mixture of the two configurations is unavoidable during the reaction. Traditional processes employ dropwise addition of boron trifluoride etherate or addition of the reactants to boron trifluoride etherate. However, this makes it difficult to suppress side reactions during scale-up.

[0004] The method disclosed in CN117624100A comprises heating and dissolving 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane, toluene, and triethylamine, and then dripping the mixture into a reactor containing boron trifluoride etherate and triethylsilane at -40°C. Dichloromethane is then added and stirred to dissolve the mixture. The mixture is kept warm for 4 hours, then slowly heated to room temperature and reacted for another 4 hours. After post-treatment, the crude product of dapagliflozin is obtained.

[0005] The method disclosed in CN104478839A comprises adding triethylsilane to an acetonitrile solution of 2-chloro-5-(1-methoxy-D-pyranose-1-yl)-4′-ethoxydiphenylmethane at -10 to 0°C, adding boron trifluoride etherate dropwise, and reacting at 0 to 5°C for 8 hours. Conventional post-treatment is then performed to obtain a crude product of dapagliflozin.

[0006] The methods disclosed in CN117624100A and CN104478839A all use a dropwise addition method, which results in poor reproducibility, amplification effects, low reaction temperature requirements, or long reaction times. These differences are significant compared to the microchannel continuous flow method for preparing crude dapagliflozin. The crude dapagliflozin prepared using microchannel continuous flow technology can be purified by acetylation and ethanol once to obtain acetylated dapagliflozin with a purity exceeding 99%. Summary of the Invention

[0007] In order to overcome the deficiencies of the prior art, the present invention provides a method for rapidly preparing a crude product of dapagliflozin based on microchannel continuous flow technology, thereby being able to synthesize the target compound safely, efficiently and stably.

[0008] Based on the above objectives, the present invention is achieved through the following technical solutions: A method for rapidly preparing a crude dapagliflozin product based on microchannel continuous flow technology. The method uses 2-chloro-5-(1-methoxy-D-glucopyranos-1-yl)-4′-ethoxydiphenylmethane and a reducing agent as raw materials, and produces a crude dapagliflozin product through a liquid-liquid two-phase reduction reaction in a microreactor. The specific steps are as follows: The reaction route is as follows: The specific steps are as follows: a mixture of an acetonitrile solution of 2-chloro-5-(1-methoxy-D-pyranoglucopyranose-1-yl)-4′-ethoxydiphenylmethane and a reducing agent, and an acetonitrile solution of boron trifluoride etherate are pumped into a microchannel reactor at a certain molar ratio, a reduction reaction is carried out at a certain temperature, and the crude product of dapagliflozin is obtained after quenching and conventional post-treatment.

[0009] Furthermore, the HPLC purity of the 2-chloro-5-(1-methoxy-D-glucopyranos-1-yl)-4′-ethoxydiphenylmethane is 90%.

[0010] Furthermore, the reducing agent is at least one of triethylsilane and triisopropylsilane, preferably triethylsilane.

[0011] Furthermore, the molar ratio of the 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane to the reducing agent is 1:3-5.

[0012] Preferably, the molar ratio of the 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane to the reducing agent is 1:3 to 3.5.

[0013] Furthermore, the molar ratio of the 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane to boron trifluoride etherate is 1:3-5.

[0014] Preferably, the molar ratio of the 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane to boron trifluoride etherate is 1:3-3.5.

[0015] Furthermore, the reduction reaction temperature is -20°C to 0°C, and the reaction residence time is 0.5min to 10min.

[0016] Preferably, the temperature of the reduction reaction is -15°C to -5°C, and the reaction residence time is 0.5 min to 5 min.

[0017] The microchannel reactor is a reaction device based on a single channel and / or multiple channels.

[0018] The beneficial effects of the present invention are as follows: The innovation of the present invention lies in converting the traditional autoclave reduction reaction into a continuous process by coupling microchannel continuous flow technology, greatly improving the selectivity of the reduction reaction, significantly increasing production efficiency, and maximally suppressing the amplification effect, thereby enabling industrial production. The microchannel reactor described in the present invention has a scale characteristic that is several orders of magnitude smaller than that of conventional autoclave reactors, and has a larger specific surface area than conventional autoclave reactors, enabling rapid removal of reaction heat from the reaction system. Therefore, the present invention enables the reaction to obtain products comparable to autoclave products under safe, environmentally friendly, efficient, and stable continuous conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a diagram of the synthesis device of the crude dapagliflozin product of the present invention; In the figure: 1. Storage tanks for acetonitrile solution of 2-chloro-5-(1-methoxy-D-glucopyranos-1-yl)-4′-ethoxydiphenylmethane and reducing agent; 2. Storage tank for acetonitrile solution of boron trifluoride etherate; 3. First metering pump; 4. Second metering pump; 5. Microchannel reactor; 6. Constant temperature bath; 7. Product receiving tank. DETAILED DESCRIPTION

[0020] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in detail below in conjunction with specific embodiments. However, it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

[0021] The technical solution of this application is described in detail below through specific embodiments: Unless otherwise specified, the technical means used in the present invention are conventional means well known to those skilled in the art. The various raw materials, reagents, instruments, and equipment used in the present invention can be purchased from the market or prepared by existing methods. Unless otherwise specified, the reagents used in the present invention are of analytical grade.

[0022] In the present invention, parts by weight may be weight units known in the art such as μg, mg, g, kg, etc., or multiples thereof, such as 1 / 10, 1 / 100, 10 times, 100 times, etc.

[0023] Example 1 A method for rapidly preparing crude dapagliflozin based on microchannel continuous flow technology, the process is as follows: like Figure 1 As shown, an acetonitrile solution of 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane (concentration of 15 mg / mL) and triethylsilane are placed in a storage tank 1 and mixed evenly; an acetonitrile solution of boron trifluoride etherate (concentration of 20 mg / mL) is placed in a storage tank 2. The solutions in storage tanks 1 and 2 are pumped into a microchannel reactor 5 by a first metering pump 3 and a second metering pump 4, respectively, for reaction. The reaction flow rate is controlled so that 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane is mixed evenly. The reaction was carried out in a microchannel reactor 5 in a constant temperature bath 6 at a temperature of -10°C to -5°C for 1 minute. The reaction solution was then collected in a product receiving tank 7. After collection, the reaction solution was quenched with a saturated sodium carbonate solution until neutral, concentrated, and extracted with dichloromethane. The resulting organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to yield an off-white solid. High-performance liquid chromatography analysis revealed a purity of 93.4% for the crude dapagliflozin product, with a yield of approximately 90.3%.

[0024] Example 2: The specific preparation process was the same as that in Example 1, except that the residence time of the microchannel reactor 5 was changed to 2 min. The purity of the crude dapagliflozin obtained was 93.7%, and the yield was 91.1%.

[0025] Example 3: The specific preparation process was the same as that in Example 1, except that the molar ratio of 2-chloro-5-(1-methoxy-D-glucopyranos-1-yl)-4′-ethoxydiphenylmethane, triethylsilane, and boron trifluoride etherate was changed to 1:3.5:3.5. The crude product of dapagliflozin obtained had a purity of 92.5% and a yield of approximately 90.7%.

[0026] Example 4: The specific preparation process was the same as that in Example 1, except that the temperature of the thermostatic bath 6 was changed to -15°C to -10°C. The purity of the crude dapagliflozin obtained was 93.6%, and the yield was about 91.5%.

[0027] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to realize and utilize a variety of exemplary embodiments of the invention and various options and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A method for rapidly preparing crude dapagliflozin based on microchannel continuous flow technology, wherein 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane and a reducing agent are used as raw materials to produce crude dapagliflozin through a liquid-liquid two-phase reduction reaction in a microreactor. The reaction route is as follows: The specific steps are as follows: a mixture of an acetonitrile solution of 2-chloro-5-(1-methoxy-D-pyranoglucopyranose-1-yl)-4′-ethoxydiphenylmethane and a reducing agent, and an acetonitrile solution of boron trifluoride etherate are pumped into a microchannel reactor at a certain molar ratio, a reduction reaction is carried out at a certain temperature, and the crude product of dapagliflozin is obtained after quenching and conventional post-treatment.

2. The method for rapidly preparing crude dapagliflozin based on microchannel continuous flow technology according to claim 1, characterized in that: The HPLC purity of the 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane is above 90%.

3. The method for rapidly preparing crude dapagliflozin based on microchannel continuous flow technology according to claim 1, characterized in that: The reducing agent is at least one of triethylsilane and triisopropylsilane.

4. The method for rapidly preparing crude dapagliflozin based on microchannel continuous flow technology according to claim 1, characterized in that: The molar ratio of the 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane to the reducing agent is 1:3-5.

5. The method for rapidly preparing crude dapagliflozin based on microchannel continuous flow technology according to claim 1, characterized in that: The molar ratio of the 2-chloro-5-(1-methoxy-D-glucopyranose-1-yl)-4′-ethoxydiphenylmethane to boron trifluoride etherate is 1:3-5.

6. The method for rapidly preparing a crude dapagliflozin product based on microchannel continuous flow technology according to any one of claims 1 to 5, characterized in that: The temperature of the reduction reaction is -20°C to 0°C, and the reaction residence time is 0.5min to 10min.

7. The method for rapidly preparing crude dapagliflozin based on microchannel continuous flow technology according to claim 6, characterized in that: The temperature of the reduction reaction is -15°C to -5°C, and the reaction residence time is 0.5min to 5min.

8. The method for rapidly preparing crude dapagliflozin based on microchannel continuous flow technology according to claim 1, characterized in that: The microchannel reactor is a reaction device based on a single channel and / or multiple channels.

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